Indoles directed lithiation

Directed -lithiation of N-substituted indoles at the 3-position has been achieved with some 2-substituted indoles. Thus for example, N-t-Bu-1-methylindole-2-carboxamide can be lithiated at C-3 with 5-BuLi and TMEDA, but when a similar reaction was attempted with the 1-ben-zenesulfonyl analog, cleavage to an acetylene occurred readily, even at -78°C (Scheme 20)(86H2127). 

The direct lithiation of benzo fused heterocyclic systems in the benzo ring is often less easy than in the heterocyclic ring or even at a substituent phenyl group. Thus, while A7-phenyl indole undergoes lithiation at both the 2- and the 2 -positions, /3-lithiation at the 7-position does not occur. The first observation of lithiation at the 7-position of an indole derivative was seen with tricarbonyl(T7 -l-methyl-2-trimethylsilylindole)chromium(0) 26, even though the major site of reaction was at C-4 (Scheme 28)... 

Gramme is a common precursor for indol-3-ylmethylation of enolates and other nucleophiles. Such reactions normally occur by an elimination-addition mechanism. Following development of procedures for 4-substitution via directed lithiation with l-(tri-/w-propylsilyl)-gramine, Iwao and Motoi have developed conditions for tandem nucleophilic substitution of the dimethylamino group. Quatemization followed by reaction with a nucleophile in the presence of TBAF leads to alkylation. <95TL5929> The carbon nucleophiles which were successfully used include nitromethane, methyl acetoacetate, diethyl malonate and diethyl 2-(acetamido)malonate. Phthalimide, thiophenol, TMS-CN and TMS-Nj were also used as sources of nucleophiles. 

Directed lithiation continues to be a versatile method for synthetic elaboration of pyrroles and indoles Conditions for lithiation of l-vinylpyrrole were explored. Lithiation with n-butyllithium with or without TMEDA or KO-f-Bu gave a mixture of C2 and o(-vinyl lithiation. Use of a catalytic amount of (/-Pr)2NH (12 mol %) with a stoichiometric amount of -butylIithium/KO-/-Bu at -60 to -80" leads to selective C2 lithiation. <95RTCl8> These conditions are believed to reflect a... 

An iterative directed-metallating approach to 4,5-substituted indoles starting from gramine was documented <05T6886>. Treatment of gramine 173 with tert-butyllithium and trimethylsilylmethylazide followed by Boc protection gave 4-aminoindole 174. Directed lithiation by the carbamate followed by treatment with DMF gave indole 175. 

The dimethylamino group of gramine directs lithiation to C-4 when the indolic nitrogen is protected by the bulky tri-i-propylsilyl group but metallation occurs normally at C-2 when this nitrogen bears a simple methyl. 

Among the less conventional substrates for lithiation are the y -chroniium complexes of indole. Lithiation occurs preferentially at C2 but can be directed to the carbocyclic ring if the 2-position is blocked. The complex of l-(methoxymethyl)indole is lithiated at position 7, if the 2-position is blocked by a TMS group. 7-Substituted indoles can be obtained in 70-95% yield <89T5955>. The chromium can be removed photochemically (Scheme 120). 

Iwao also observed direct lithiation at C3 with A-(2,2-diethylbutanoyl)indole 9b (Table 13, entries 5-8) [18]. The yields obtained with the DEB-protecting group were somewhat lower than those obtained with the TIPS-protecting group. The optimal reaction conditions included hexane as the solvent much lower yields were obtained when the reactions were run in ether. When superbase was used (sec-BuLi - - t-BuOK), lithiation of 9b occurred preferentially at C2. 

Although most A-(substituted)indoles are selectively lithiated at C2, a few protecting groups have been found to selectively direct lithiation at C7 even in the absence of groups at C2. Iwao found that the DEB (2,2-diethylbutanoyl) group directed lithiation to C7 [18]. This reaction was synthetically useful for 3-(substituted)indole... 

In the same series of papers, Knight also investigated the selective C2-lithiation of indole-3-carboxamides [326, 327]. In this case, n-butyllithium (slight excess) was used as the base instead of LDA. Treatment of indole-3-carboxamides 103 with n-butyllithium followed by electrophiles gave 2,3-(disubstituted)indoles 104. A portion of the results obtained are shown below (Table 20). Snieckus used a directed lithiation of 103c to prepare the corresponding indole-2-boronic acid, a useful building block for the synthesis of indolocarbazoles [329]. 

Gribble was the first to investigate the use of a C2-based DMG (pyridyl) to direct lithiation to the C3 position of the indole ring [332]. Treatment of 2-pyridylindole... 

Amazingly, Iwao reports that l-(triisopropylsilyl)indole can be directly lithiated at the C-3 position with rert-BuLi-TMEDA in hexane at 0°C <01TL7621>. Furthermore, this author also describes an unusual C-3 lithiation of indoles 149 bearing the 2,2-diethylbutanolyl... 

Wender and White published a very simple indole ring synthesis that involves the generation of a bis-lithio anion 1 and its reaction with an a-halo carbonyl compound 2, followed by acid- or base-catalyzed dehydration [1,2], The overall transformation is shown in Scheme 1, along with three examples. This chemistry illustrates yet another indole ring synthesis that uses a-halo carbonyl compounds [3]. We will encounter these compounds again with the venerable Bischler indole synthesis in Chapter 23. A summary of several Wender indole ring syntheses is tabulated in Table 1 [1, 2, 4-7], Entry 5 features a directed lithiation method to the bis-lithio nucleophile [5], a modification also described by Wender and White [2], Sainsbury and... 

Iwao et d. introduced an efficient methodology ftH the synthesis of 3,4-disubstituted indoles 113 (57). Their strategy comprises two sequential steps 1) selective functionalization of l-silyl-3-dimethylaminomethylindole (111) at the 4-position by directed lithiation, followed by quenching with electrophiles, for the preparation of 4-dimethylamino-substituted indole 112 (58) 2) substitution of the dimethylamino group of 112 for various nucleophiles giving 113 upon desilylation through quatemization followed by a fluoride ion-induced elimination-addition reaction (Scheme 17) (59). 

Introduction of an iodine to C-2 of indole can be accomplished using lithium derivatives. Since direct iodination tends to give mixtures it is essential to activate the 2-position at the expense of the inherently more reactive 3-position. This has been done by lithiating 1-f-butoxycarbonylin-doles (25) and then converting them into iodo derivatives before deprotection (85JHC505) (Scheme 19). Alternatively carbon dioxide can be used... 

In continuation of his extraordinarily versatile and efficient directed-metalation technology, Snieckus employed indole 87 to selectively lithiate C-4 and to effect a Negishi coupling with 3-bromopyridine to give 88 in 90% yield [110]. In contrast, a Suzuki protocol gave 88 in only 19% yield (with loss of the TBS group). 

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